In recent years, through the work of our lab and others, it has become increasingly clear that the posterior cingulate cortex (PCC) is affected early in Alzheimer's Disease (AD). This renewal application continues to focus on the PCC in preclinical AD. With prior VA funding, we used functional MRI (fMRI) to study brain activity during metacognition and episodic recollection using paradigms that activate the healthy PCC. We have found that PCC fMRI activity is affected by risk factors for AD including mild cognitive impairment, apolipoprotein e4 (APOE4) genetic status, and parental family history (PFH) of AD. However, fMRI is complex, and a simpler, more widely available type of scan may be more ideal. In this application, we will examine resting cerebral blood flow (CBF) or perfusion in people at risk. HYPOTHESIS: The overall hypothesis is that the PCC will exhibit reduced CBF in middle-aged adults with AD risk factors including cognitive decline, APOE4 status, and PFH status and that reduced CBF over a two-year follow-up period will be related to cognition and fMRI signal. STUDY DESIGN: This 4-year project will capitalize on very recent advances in a noninvasive perfusion MRI method known as pseudo-continuous arterial spin labeling (ASL) to determine if asymptomatic people at risk for AD exhibit quantitative CBF decrements associated with risk factor status or observed cognitive decline. This would extend prior AD and MCI research with ASL to asymptomatic people at risk in a unique, important preMCI cohort that has PFH for AD and that undergoes detailed cognitive testing every 4 years. AIM 1: To determine whether longitudinal decline in memory functioning is explained by baseline or longitudinal decline in CBF in the PCC. This component of the project will allow us the unique and rare opportunity to examine the brain with regard to longitudinal change from normal to MCI in otherwise healthy, late middle-aged adults. AIM 2: To determine whether reductions in CBF in the PCC occur prior to cognitive decline, and whether such CBF reductions may be attributable to AD risk factors. AIM 3: To examine the relationship between fMRI signal during recognition memory and CBF in the PCC, and also to examine cognitive profiles that may result in different CBF patterns. AIM 4: To examine the long-term cognitive decline (4 years) and PCC BOLD response in data previously collected. METHODS: To accomplish these aims, we will recruit a sample of 200 subjects from the Wisconsin Registry for AD Prevention (WRAP), a large cohort of 1,200 participants who are followed longitudinally. We will select appropriate subjects from this registry for ASL and fMRI scanning. We will examine CBF and fMRI activity in the PCC using a unified approach with voxel-based multivariate statistics to determine the relationship between cognitive decline, APOE4, and PFH risk factors and cerebral blood flow. SIGNIFICANCE FOR VETERANS: More than one-third of the nation's veterans are over age 65, and better methods for early detection of AD are urgently needed to characterize brain changes prior to dementia symptom onset so that interventions can begin sooner. PUBLIC HEALTH RELEVANCE: The Office of Research and Development of the VA has designated aging and problems of aging as one of its research priorities. With the aging veterans population, problems associated with aging, including dementias, will continue to be a public health burden. Methods are needed for disambiguating aging syndromes such as cognitive difficulties from early AD. Early identification and treatment of AD may prolong stable cognitive function and reduce the financial burden to VA and public healthcare systems associated with the increasing prevalence of AD with age. From the 2000 Census, there were 26.5 million total veterans, 9.7 million veterans are over age 65, while 16.8 million veterans are all younger. This means that more than 1/3rd of veterans are over 65. These numbers are expected to increase as the population ages (though the number of young veterans is now increasing, too), and average lifespan increases, making prevalence of AD and related neurodegenerative disease a growing problem. In the recently published President's Task Force To Improve Health Care Delivery to Our Nation's Veterans, an important problem facing the VA system is highlighted in Chapter Five: the mismatch between increasing demand for access to care through the VAH, and financial resources to meet this need. Early identification of AD and other dementias will serve to reduce this discrepancy and to relieve the overall economic burden of this disease to the U.S. and the VA health care system.